Lung macrophages represent a key first line defense against pathogens. Macrophages sense microbes that induce the production, processing and release of the proinflammatory cytokine IL-1beta. Regulation of IL-1beta is fundamental to many types of lung inflammatory diseases including acute lung injury and sepsis. In this context, macrophages are suppressed in their ability to process and release IL-1beta compared to monocytes. This is despite the fact that, after endotoxin challenge, macrophages contain abundant precursor IL-1beta and caspase-1. Recently, a new class of host defense molecules has been described that may shed light on this important difference. These proteins, termed CATERPILLERs, are homologues of plant disease resistance genes. They contain CARD and PYRIN domains that direct molecular groupings. One such grouping, termed the inflammasome, regulates the ability of caspase-1 to cleave the precursors of IL-1beta and IL-18 to their functional forms. This led us to hypothesize that modifications of the inflammasome dictate innate host responses in macrophages. Preliminary data presented here show that signaling through tyrosine kinase and JAK/STAT pathways can respectively activate or suppress function of the inflammasome. Therefore, to determine the specifics of this central innate host response, this application uses the monocyte macrophage difference to discover key inflammasome structure function relationships. Specifically, this proposal will 1) determine the role of CARD and PYRIN domain proteins as regulators of IL-1beta release during monocyte maturation; 2) test the hypothesis that JAK/STAT pathways induce functional changes in the inflammasome; 3) determine how certain CATERPILLER proteins inhibit function of the inflammasome; and 4) test the hypothesis that tyrosine kinase activity is required for correct inflammasome assembly. Successful completion of these aims will provide novel insights into innate host responses and create new therapeutic opportunities to prevent and treat inflammatory lung diseases.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Harabin, Andrea L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Hoang, Ky V; Rajaram, Murugesan V S; Curry, Heather Marie et al. (2018) Complement Receptor 3-Mediated Inhibition of Inflammasome Priming by Ras GTPase-Activating Protein During Francisella tularensis Phagocytosis by Human Mononuclear Phagocytes. Front Immunol 9:561
Ratner, Dmitry; Orning, M Pontus A; Proulx, Megan K et al. (2016) The Yersinia pestis Effector YopM Inhibits Pyrin Inflammasome Activation. PLoS Pathog 12:e1006035
Hoyt, Laura R; Ather, Jennifer L; Randall, Matthew J et al. (2016) Ethanol and Other Short-Chain Alcohols Inhibit NLRP3 Inflammasome Activation through Protein Tyrosine Phosphatase Stimulation. J Immunol 197:1322-34
Shamaa, Obada R; Mitra, Srabani; Gavrilin, Mikhail A et al. (2015) Monocyte Caspase-1 Is Released in a Stable, Active High Molecular Weight Complex Distinct from the Unstable Cell Lysate-Activated Caspase-1. PLoS One 10:e0142203
Sundaram, Kruthika; Mitra, Srabani; Gavrilin, Mikhail A et al. (2015) House Dust Mite Allergens and the Induction of Monocyte Interleukin 1? Production That Triggers an I?B?-Dependent Granulocyte Macrophage Colony-Stimulating Factor Release from Human Lung Epithelial Cells. Am J Respir Cell Mol Biol 53:400-11
Mitra, Srabani; Wewers, Mark D; Sarkar, Anasuya (2015) Mononuclear Phagocyte-Derived Microparticulate Caspase-1 Induces Pulmonary Vascular Endothelial Cell Injury. PLoS One 10:e0145607
Rahman, Mohd Akhlakur; Sundaram, Kruthika; Mitra, Srabani et al. (2014) Receptor interacting protein-2 plays a critical role in human lung epithelial cells survival in response to Fas-induced cell-death. PLoS One 9:e92731
Ghonime, Mohammed G; Shamaa, Obada R; Das, Srabani et al. (2014) Inflammasome priming by lipopolysaccharide is dependent upon ERK signaling and proteasome function. J Immunol 192:3881-8
Liu, Ming-Jie; Bao, Shengying; Gálvez-Peralta, Marina et al. (2013) ZIP8 regulates host defense through zinc-mediated inhibition of NF-?B. Cell Rep 3:386-400
Gillette, Devyn D; Shah, Prexy A; Cremer, Thomas et al. (2013) Analysis of human bronchial epithelial cell proinflammatory response to Burkholderia cenocepacia infection: inability to secrete il-1?. J Biol Chem 288:3691-5

Showing the most recent 10 out of 24 publications